Outline

Multiple sclerosis (MS) is the most frequent demyelinating disease of the CNS. Histopathologically, the disease is characterized by inflammation, demyelination and gliosis. Axonal damage and loss are the underlying causes for permanent neurological disability in MS. Limited remyelination contributes to axonal damage by increased vulnerability of demyelinated axons to immune mediated damage and lack of trophic support. The continuous stimulation of the canonical Wnt/b-catenin (cWbC) pathway impairs differentiation of oligodendrocytes (OL) and prevents thereby remyelination in demyelinating animal models of MS. Non-steroidal anti-inflammatory drug, such as Indomethacin (IM) and AspirinÂ® (ASS), attenuate b-catenin signaling activity either by phosphorylation of b-catenin via GSK3b or by disruption of the interaction between b-catenin with its nuclear coactivator TCF4.

Therefore, the aim of this study is to determine which effects ASS and IM have on OL differentiation, process formation and myelin gene expression (MGE). Also, we analyze the expression patterns of different components of the cWbC pathway in MS lesions to understand the impact of this signaling cascade on remyelination. ASS has no effect on process formation and does not promote MGE in primary murine OL. In contrast, exposure of OL to 2.5 ÂµM IM for 48 hours increases MGE, but has no effect on process formation. Further experiments are required to determine whether the increased myelin gene levels induced by IM are mediated by cWbC pathway activation. To gain insight into the contribution of the cWbC pathway to remyelination in MS, we analyzed the expression patterns of different components in MS lesions. TCF4 is expressed in OL and astrocytes in a subset of early MS lesions, but can also be detected in tissue samples from patients with inflammatory, non-demyelinating diseases, such as vasculitis and encephalitis. In contrast, in chronic disease stage tissue samples, no expression of TCF4 was detected. By WB we detected slightly increased b-catenin levels in MS lesions compared to normal appearing white matter. Our results suggest that IM, but not ASS increases the expression of myelin genes. Further experiments are required to determine the functional role of the cWbC pathway for OL differentiation and remyelination in OL and MS.